Gao Xuan, Fan Youli, Wang Guijia, Xu Jiangjiang, Deng Runwei, Song Jiangwei, Sun Binfeng, Wang Yongbing, Wu Zixuan, Jia Ruyi, Huang Jing, He Huiyu, Gao Lei, Zhang Yihao, Sun Na, Wu Bingxiang
Department of Cardiology, The Key Laboratory of Myocardial Ischemia, Ministry of Education, The Second Affiliated Hospital of Harbin Medical University, NO.246 Xuefu Road, Nangang District, Harbin, 150086, China.
Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150086, China.
J Transl Med. 2025 Mar 26;23(1):373. doi: 10.1186/s12967-025-06373-x.
Abnormal glycolytic metabolism plays a significant role in pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH), yet the specific mechanisms remain unclear. The primary objective of this study is to investigate the key regulatory mechanisms of glycolysis in IPAH.
Bulk and single-cell sequencing data obtained from IPAH patient tissue samples were downloaded from the GEO database. scMetabolism and AUCcell analyses of the IPAH single-cell sequencing data were carried out to quantify the glycolytic metabolic activity and identify the main cell types regulating glycolysis, respectively. The ssGSEA method was used to assess the glycolytic activity in each bulk sample within the bulk sequencing data. Differential analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network analysis were conducted to identify key genes associated with glycolysis in IPAH samples. Single-cell sequencing and a monocrotaline (MCT)-induced model of PH in rats were utilized to validate the expression of these key genes.
Single-cell sequencing data indicated that IPAH patients displayed increased glycolytic activity, which was primarily regulated by fibroblasts. Similarly, bulk transcriptomic data revealed a significant increase in glycolytic activity in IPAH patients. Differential analysis, WGCNA, PPI network analysis, and integrated single-cell analysis further identified insulin-like growth factor-1 (IGF1), lysyl-tRNA synthetase (KARS), caspase-3 (CASP3), and cyclin-dependent kinase inhibitor 2 A (CDKN2A) as key genes associated with fibroblast-mediated glycolysis in IPAH patients. Differential expression of IGF1, KARS, CASP3, and CDKN2A was also observed in our in vivo model of PH.
Our study identifies IGF1, KARS, CASP3, and CDKN2A as key regulatory genes in glycolysis in IPAH, which provides the basis for the development of targeted therapies.
异常糖酵解代谢在特发性肺动脉高压（IPAH）的肺血管重塑中起重要作用，但其具体机制仍不清楚。本研究的主要目的是探讨IPAH中糖酵解的关键调控机制。
从GEO数据库下载IPAH患者组织样本的批量和单细胞测序数据。对IPAH单细胞测序数据进行scMetabolism和AUCcell分析，分别量化糖酵解代谢活性并鉴定调节糖酵解的主要细胞类型。采用ssGSEA方法评估批量测序数据中每个批量样本的糖酵解活性。进行差异分析、加权基因共表达网络分析（WGCNA）和蛋白质-蛋白质相互作用（PPI）网络分析，以鉴定IPAH样本中与糖酵解相关的关键基因。利用单细胞测序和大鼠野百合碱（MCT）诱导的肺动脉高压模型验证这些关键基因的表达。
单细胞测序数据表明，IPAH患者的糖酵解活性增加，主要由成纤维细胞调节。同样，批量转录组数据显示IPAH患者的糖酵解活性显著增加。差异分析、WGCNA、PPI网络分析和综合单细胞分析进一步确定胰岛素样生长因子-1（IGF1）、赖氨酰-tRNA合成酶（KARS）、半胱天冬酶-3（CASP3）和细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）是IPAH患者中与成纤维细胞介导的糖酵解相关的关键基因。在我们的肺动脉高压体内模型中也观察到IGF1、KARS、CASP3和CDKN2A的差异表达。
我们的研究确定IGF1、KARS、CASP3和CDKN2A是IPAH糖酵解中的关键调控基因，为靶向治疗的开发提供了依据。
